Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological hypertrophy signaling.
Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological hypertrophy signaling.
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DOI：
10.1016/j.yjmcc.2012.08.005
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发表时间：
2012-11
影响因子：
5
通讯作者：
Houser SR
中科院分区：
文献类型：
--
作者：
Gao H;Wang F;Wang W;Makarewich CA;Zhang H;Kubo H;Berretta RM;Barr LA;Molkentin JD;Houser SR
常见的心血管疾病，如高血压和心肌梗死，需要心肌细胞发育到比正常水平更大的力量来维持心泵功能。这需要增加[钙离子]。这些疾病导致心肌肥大，而钙离子的增加被认为是肥大基因激活的重要近端信号。然而，肥大的[Ca~(2+)]的来源尚不清楚，这是本研究的主题。研究了通过L钙通道、T型钙通道和瞬时受体电位通道的钙内流在钙调神经磷酸酶-核因子活化T细胞信号通路和心肌细胞肥大中的作用。用含NFAT-GFP的腺病毒感染新生大鼠(NRVMs)和成年猫(AFVM)的心肌细胞，以确定诱导NFAT核转位的因素。4毫米尔钙离子或起搏诱导NFAT核移位。这一作用可被CN抑制剂阻断。在NRVM中，硝苯地平(Nif，LTCC拮抗剂)可阻断高钙诱导的NFAT核转位，而Trp通道拮抗剂SKF-96365和镍(Ni，TTCC拮抗剂)的作用较弱。这些拮抗剂对钙离子诱导的NFAT核转位(NIF>；SKF-96365和GT；Ni)的相对效力与它们对钙瞬变和LTCC电流的影响相似。含有Trp通道的病毒感染NRVM后，也激活了NFAT-GFP核转位，导致心肌细胞肥大。SKF-96365可减弱色氨酸的作用，但能更有效地拮抗NIF的作用。这些实验表明，钙离子通过LTCCs的内流是激活NRVM和AFVM中CN-NFAT信号的主要钙来源。虽然Trp通道导致肥厚，但它们似乎是通过一种涉及钙离子通过LTCC进入的机制来实现的。
Common cardiovascular diseases such as hypertension and myocardial infarction require that myocytes develop greater than normal force to maintain cardiac pump function. This requires increases in [Ca2+]. These diseases induce cardiac hypertrophy and increases in [Ca2+] are known to be an essential proximal signal for activation of hypertrophic genes. However, the source of “hypertrophic” [Ca2+] is not known and is the topic of this study. The role of Ca2+ influx through L-type Ca2+ channels (LTCC), T-type Ca2+ channels (TTCC) and transient receptor potential (TRP) channels on the activation of Calcineurin (Cn) – Nuclear Factor of Activated T cells (NFAT) signaling and myocyte hypertrophy was studied. Neonatal rat (NRVMs) and adult feline (AFVM) ventricular myocytes were infected with an adenovirus containing NFAT-GFP, to determine factors that could induce NFAT nuclear translocation. Four millimolar Ca2+ or pacing induced NFAT nuclear translocation. This effect was blocked by Cn inhibitors. In NRVMs Nifedipine (Nif, LTCC antagonist) blocked high Ca2+-induced NFAT nuclear translocation while SKF-96365 (TRP channel antagonist) and Nickel (Ni, TTCC antagonist) were less effective. The relative potency of these antagonists against Ca2+ induced NFAT nuclear translocation (Nif>SKF-96365>Ni) was similar to their effects on Ca2+ transients and the LTCC current. Infection of NRVM with viruses containing TRP channels also activated NFAT-GFP nuclear translocation and caused myocyte hypertrophy. TRP effects were reduced by SKF-96365, but were more effectively antagonized by Nif. These experiments suggest that Ca2+ influx through LTCCs is the primary source of Ca2+ to activate Cn-NFAT signaling in NRVMs and AFVMs. While TRP channels cause hypertrophy, they appear to do so through a mechanism involving Ca2+ entry via LTCCs.